Enantiospecific cyclization of methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate to 2-methylproline derivative via ‘memory of chirality’ in flow
Abstract
We report for the very first time a continuous-flow route to perform the intramolecular cyclization of haloalkyl-substituted α-amino esters via memory of chirality (MoC), using lithium bis(trimethylsilyl)amine as a base and methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate as a model reactant. The various reaction parameters, such as temperature, residence time, reactant stoichiometry, or type and concentration of the base were optimized to maximize the yield of the cyclized product and its enantiomeric excess. At the conditions identified, the reaction was eventually scaled up, reaching a productivity of 11 g h−1. Compared to the standard batch protocols available in the literature, the use of a microreactor enables a better control of the exothermicity associated with the addition of the organolithium reagent to the reaction mixture, resulting in operations at more practical temperatures, with high enantiospecificity and full conversion of the reactive amino ester within a few seconds of residence time.
ᅟ
Keywords
Flow chemistry Asymmetric synthesis Cyclization Microreactors Memory of chiralityAbbreviations
- F16
flow rate in mL min−1 of compound 16 in a solution of DMF
- Fbase
flow rate in mL min−1 of the base solution
- T
reaction temperature
- Boc
tert-butyloxycarbonyl
- LC
liquid chromatography
- GC
gas chromatography
- MS
mass spectrometry
- NMR
nuclear magnetic resonance
- X
conversion of 16
- ee
enantiomeric excess
Notes
Acknowledgements
We are grateful to Dr. Simone Tortoioli for proof-reading the manuscript and for valuable comments. The authors would like to thank Julien Grimont for NMR support, as well as Claus Mueller and his team for analytical methods and chiral analyses. Finally, Dr. Thomas Weller is sincerely acknowledged for support and comments on the paper.
Supplementary material
References
- 1.Park K-H, Kurth MJ (2002). Tetrahedron 58:8629CrossRefGoogle Scholar
- 2.Kano T, Sakamoto R, Mii H, Wang Y-G, Maruoka K (2010). Tetrahedron 66:4900CrossRefGoogle Scholar
- 3.Kawabata T, Yahiro K, Fuji K (1991). J. Am. Chem. Soc. 113:9694CrossRefGoogle Scholar
- 4.Zhao H, Hsu DC, Carlier PR (2005). Synthesis 1:1Google Scholar
- 5.Seebach D, Naef R (1981). Helv. Chim. Acta 64:2704CrossRefGoogle Scholar
- 6.Seebach D, Sting AR, Hoffmann M (1996). Angew. Chem. Int. Ed. 35:2708CrossRefGoogle Scholar
- 7.Branca M, Gori D, Guillot R, Alezra V, Kouklovsky C (2008). J. Am. Chem. Soc. 130:5864CrossRefGoogle Scholar
- 8.Schmalz H-G, de Konig CB, Bernicke D, Siegel S, Pfletschinger A (1999). Angew. Chem. Int. Ed. 38:1620CrossRefGoogle Scholar
- 9.Buckmelter AJ, Kim AI, Rychnovsky SD (2000). J. Am. Chem. Soc. 122:9386CrossRefGoogle Scholar
- 10.Giese B, Wettsein P, Stähelin C, Barbosa F, Neuburger M, Zenher M, Wessig P (1999). Angew. Chem. Int. Ed. 38:2586CrossRefGoogle Scholar
- 11.Kolaczkowski L, Barnes DM (2007). Org. Lett. 9:3029CrossRefGoogle Scholar
- 12.Hicks F, Hou Y, Langston M, McCarron A, O’Brien E, Ito T, Ma C, Matthews C, O’Bryan C, Provencal D, Zhao Y, Huang J, Yang Q, Heyang L, Johnson M, Sitang Y, Yuqiang L (2013). Org. Process. Res. Dev. 17:829CrossRefGoogle Scholar
- 13.Macharia J, Wambua V, Hong Y, Harris L, Hirschi JS, Evans GB, Vetticatt MJ (2017). Angew. Chem. Int. Ed. 56:8756CrossRefGoogle Scholar
- 14.Salmon AG, Kizer KW, Zeise L, Jackson RJ, Smith MT (1995). J. Toxicol. Clin. Toxicol. 33:115CrossRefGoogle Scholar
- 15.Wu G, Huang M (2014). Org. Process. Res. Dev. 18:1192CrossRefGoogle Scholar
- 16.Kawabata T, Kawakami S, Majumdar S (2003). J. Am. Chem. Soc. 125:13012CrossRefGoogle Scholar
- 17.Kawabata T, Wirth T, Yahiro K, Suzuki H, Fuji K (1994). J. Am. Chem. Soc. 116:10809CrossRefGoogle Scholar
- 18.Kawabata T, Matsuda S, Kawakami S, Monguchi D, Moriyama K (2006). J. Am. Chem. Soc. 128:15394CrossRefGoogle Scholar
- 19.Kawabata T, Moriyama K, Kawakami S, Tsubaki K (2008). J. Am. Chem. Soc. 130:4153CrossRefGoogle Scholar
- 20.Pastre JC, Browne DL, Ley SV (2013). Chem. Soc. Rev. 42:8849CrossRefGoogle Scholar
- 21.Baumann M, Baxendale IR, Beilstein J (2015). Org. Chem. 11:1194Google Scholar
- 22.Vilé G, Richard-Bildstein S, Lhuillery A, Rueedi G (2018). ChemCatChem 10:3786–3794Google Scholar
- 23.Abele S, Höck S, Schmidt G, Funel J-A, Marti R (2012). Org. Process. Res. Dev. 16:1114CrossRefGoogle Scholar
- 24.Amann F, Frank M, Rhodes M, Robinson A, Kesselgruber M, Abele S (2016). Org. Process. Res. Dev. 20:446CrossRefGoogle Scholar
- 25.Kockmann N, Thenée P, Fleischer-Trebes C, Laudadio G, Noël T (2017). React. Chem. Eng. 2:258CrossRefGoogle Scholar
- 26.Glasnov TN, Kappe CO (2011). Chem. Eur. J. 17:11956CrossRefGoogle Scholar
- 27.Yoshida J, Takahashia Y, Nagaki A (2013). Chem. Commun. 49:9896CrossRefGoogle Scholar
- 28.Yoshida J, Kim H, Nagaki A (2017). J. Flow. Chem. 7:60CrossRefGoogle Scholar
- 29.For general methods to prepare 16, see: (i) Kachkovskyi G, Faderl C, Reiser O (2013). Adv. Synth. Catal. 355:2240; (ii) Anxionnat B, Robert B, George P, Ricci G, Perrin MA (2012). J. Org. Chem. 77:6087Google Scholar
- 30.The chiral analysis of 16 was performed by analyzing the starting material using the method reported in the Supporting Information, and comparing this with a racemic mixture containing both 16 and ent -16 Google Scholar
- 31.Sapse AM, von Ragué Schleyer P (1995) Lithium Chemistry – a Theoretical and Experimental Overview. Wiley, New York, p 145Google Scholar
- 32.Hessel V, Kralisch D, Kockmann N, Noël T, Wang Q (2013). ChemSusChem 6:746CrossRefGoogle Scholar
- 33.Wegner J, Ceylan S, Kirschning A (2012). Adv. Synth. Catal. 354:17CrossRefGoogle Scholar
- 34.Fogler, H. Elements of chemical reaction engineering 1992, 2nd edition. Prentice Hall, Upper Saddle RiverGoogle Scholar
- 35.Singh R, Panda G (2013). RSC Adv. 3:19533CrossRefGoogle Scholar